Gastric retention systems for delivery of active agents in the upper part of the gastrointestinal tract are well known. Some active agents show preferential solubility and/or absorption in the stomach or the proximal part of the gastrointestinal tract. In such cases, gastric retention systems can deliver active agents at their preferred site of absorption, thereby improving bioavailability and reducing wastage. Such systems also find application for delivery of actives which act locally in the gastric and proximal intestinal regions, such as antacids, anti-ulcer agents etc. Other applications include delivery of active agents which exhibit a narrow absorption window, which degrade in the colon and which are poorly soluble at an alkaline pH.
Various approaches have been used to formulate systems which exhibit a prolonged gastric retention. These approaches include utilization of mechanisms such as bioadhesion (Jackson et al, Comparative scintigraphic assessment of the intragastric distribution and residence of cholestyramine, Carbopol 934P and sucralfate, Int J Pharm, 212, 2001; U.S. Pat. No. 6,207,197; United States Patent Application No. 20050064027), swelling (Chavanpatil M et al, Development of sustained release gastroretentive drug delivery system for ofloxacin: in vitro and in vivo evaluation, Int J Pharm, 304(1-2), 2005), floatation (Arora S. et al, Floating Drug delivery systems: A review, AAPS PharmSciTech 6, (3), Art. 47, 2005), sedimentation, rafts and unfolding systems (Hampson F. et al, Alginate rafts and their characterization, Int J. Pharm. 294(1-2), 2005) and simultaneous administration of gastro active agents.
An approach for increasing the gastric residence time is to produce floating systems. These systems have a density less than the gastric fluids and hence they are buoyant, i.e. they tend to float in the stomach. Since the pylorus i.e. the exit to the intestines, is located in the lower part of the stomach, they are not discharged into the intestines for a long period of time.
A mechanism to produce floatation is to produce effervescent systems. (Dave et al, Gastroretentive Drug Delivery System of Ranitidine Hydrochloride: Formulation and In Vitro Evaluation, AAPS PharmSciTech, 5, 2, Article 34, 2004; Ichikawa M, et al, A new multiple unit oral floating dosage system. 1: Preparation and in vitro evaluation of floating and sustained-release kinetics, J Pharm Sci, 80, 1991; Ozdemir N et al, Studies of floating dosage forms of furosemide: in vitro and in vivo evaluation of bilayer tablet formulation, Drug Dev Ind Pharm. 26, 2000). These systems utilize gas-generating materials, such as carbonates. On reacting with the gastric acids, the materials generate carbon dioxide, which inflates the systems and allows them to float. Such systems are however highly dependant on gastric conditions, such as acidity, for successful functioning. An approach to make them independent of gastric acids is to incorporate pharmaceutically acceptable acidic substances, with basic substances into the formulations, and allowing them to react when the system comes in contact with a fluid, such as the gastric fluid. These systems, however, generally become moisture sensitive and present mechanical and chemical stability problems, making their manufacturing and packaging cumbersome.
Another approach is to incorporate a buoyant material into a system, which causes it to float. Hydrophobic materials, such as lipids, oils and waxes are used for these purposes. (Sriamornsak P. et al, Morphology and Buoyancy of Oil-entrapped Calcium Pectinate Gel Beads, The AAPS Journal, 6, 3, 2004; Shimpi S, et al, Preparation and evaluation of diltiazem hydrochloride-Gelucire 43/01 floating granules prepared by melt granulation, AAPS PharmSciTech. 5, E43, 2004).
Matrix type and bilayer systems are known which utilize swellable materials such as polymers, hydrocolloids etc. (U.S. Pat. No. 5,232,704). The swellable materials, such as alginate, polymers, gums swell on coming in contact with fluids, reduce the density of the system and causes it to float. The increase in size of the system may also present a mechanical barrier preventing exit through the pylorus. However, in practical use, these systems often exhibit inadequate performance, reproducibility issues or need elaborate processing requirements. Also, the functional materials used are often not biodegradable. As a result, a ghost of the system remains, which may pass through the intestines unchanged and cause unacceptable blockages.
Most of these above mechanisms require the presence of fluids to activate their floatation characteristics. They tend to be dependant on gastric conditions to function effectively. But gastrointestinal conditions are inherently highly variable. The conditions depend upon and vary with many physiological factors such as diet, fluid intake, age, gender, stress conditions and disease states. Hence, although successful in in-vitro conditions, many such systems fail to function effectively in the human physiology.
To overcome some of the above mentioned problems, dosage forms such as hollow or light microcapsules and beads have been formulated. (Kawashima et al, Hollow microspheres for use as a floating controlled drug delivery system in the sto mach, J Pharm Sci, 81, (2), 1992; Patel et al, In vitro Evaluation and Optimization of Controlled Release Floating Drug Delivery System Of Metformin Hydrochloride, DARU, 14, 2, 2006; Talukder R et al, Gastroretentive Delivery Systems Hollow Beads, Drug Development and Industrial Pharmacy, 30, 4, 2004; Streubel A et al, Floating microparticles based on loss density foam powder, Int J Pharm, 241, 2002; U.S. Pat. No. 6,207,197). Although these systems are less dependant on gastric conditions, they often utilize specialized and costly raw materials and involve elaborate complex; variable and time consuming processes, which are expensive and not too scale-up friendly.
Aerogels and foam materials have been used to produce floating systems. Due to entrapped air and gases in their hollow spaces, they are inherently less dense and hence float on the gastric fluids. U.S. Pat. No. 5,626,876 discloses floatable oral therapeutic systems which use microporous materials having a high void proportion for obtaining low specific gravity. The materials used are thermoplastic polymers, natural polymers and inorganic compounds such as glasses and ceramic materials. The invention relates to preparation of microporous materials by processes such as granulation, hot melting, compression or molding. U.S. Pat. No. 3,976,764 discloses solid therapeutic preparations floatable in the gastric juice wherein the active ingredient is impregnated into a body of empty globular shell or a small granular lump of a material having high buoyancy. The empty shells of the invention are gelatin capsules coated with active ingredients. The invention also discloses pop-corn or pop-rice type of materials coated with active ingredients. Use of microporous materials tends to increase the bulk of the systems. There is also less flexibility for designing the dosage form and incorporating active ingredients. Such systems may also be complex and less reproducible.
There is a need in the art to formulate a system which overcomes most of the above mentioned disadvantages, and is yet simple, safe, easy to manufacture and is functionally reproducible. Especially, there is a need for a system which does not depend on gastric conditions for it proper functioning.